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Multi-target-directed therapeutic potential of 7-methoxytacrine-adamantylamine heterodimers in the Alzheimer's disease treatment
- Source :
- Biochimica et biophysica acta. Molecular basis of disease. 1863(2)
- Publication Year :
- 2016
-
Abstract
- Alzheimer's disease (AD) is a progressive neurodegenerative disorder and currently there is no efficient treatment. The classic drug-design strategy based on the “one-molecule-one-target” paradigm was found to be ineffective in the case of multifactorial diseases like AD. A novel multi-target-directed ligand strategy based on the assumption that a single compound consisting of two or more distinct pharmacophores is able to hit multiple targets has been proposed as promising. Herein, we investigated 7-methoxytacrine - memantine heterodimers developed with respect to the multi-target-directed ligand theory. The spectroscopic, microscopic and cell culture methods were used for systematic investigation of the interference of the heterodimers with β -secretase (BACE1) activity, A β peptide amyloid fibrillization (amyloid theory) and interaction with M1 subtype of muscarinic (mAChRs), nicotinic (nAChRs) acetylcholine receptors (cholinergic theory) and N -methyl- d -aspartate receptors (NMDA) (glutamatergic theory). The drug-like properties of selected compounds have been evaluated from the point of view of blood-brain barrier penetration and cell proliferation. We have confirmed the multipotent effect of novel series of compounds. They inhibited effectively A β peptide amyloid fibrillization and affected the BACE1 activity. Moreover, they have AChE inhibitory potency but they could not potentiate cholinergic transmission via direct interaction with cholinergic receptors. All compounds were reported to act as an antagonist of both M1 muscarinic and muscle-type nicotinic receptors. We have found that 7-methoxytacrine - memantine heterodimers are able to hit multiple targets associated with Alzheimer's disease and thus, have a potential clinical impact for slowing or blocking the neurodegenerative process related to this disease.
- Subjects :
- 0301 basic medicine
Xenopus
CHO Cells
Pharmacology
Receptors, N-Methyl-D-Aspartate
03 medical and health sciences
Cricetulus
Alzheimer Disease
Muscarinic acetylcholine receptor
medicine
Amantadine
Animals
Cholinesterases
Humans
Receptors, Cholinergic
Molecular Targeted Therapy
Enzyme Inhibitors
Molecular Biology
Acetylcholine receptor
Amyloid beta-Peptides
biology
Chemistry
Receptor, Muscarinic M1
Memantine
030104 developmental biology
Nicotinic agonist
HEK293 Cells
biology.protein
Tacrine
Molecular Medicine
NMDA receptor
Cholinergic
Pharmacophore
Amyloid Precursor Protein Secretases
Amyloid precursor protein secretase
Dimerization
medicine.drug
Subjects
Details
- ISSN :
- 09254439
- Volume :
- 1863
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Biochimica et biophysica acta. Molecular basis of disease
- Accession number :
- edsair.doi.dedup.....84ec3dd3160a835148192c7d46d95621